• Biomolecules & Therapeutics
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• v.28 no.3
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• pp.267-271
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• 2020

Gut microbiota produce dietary metabolites such as short-chain fatty acids, which exhibit anti-inflammatory effects. Free fatty acid receptor 2 (FFA2, formerly known as GPR43) is a specific receptor for short-chain fatty acids, such as acetate that regulates inflammatory responses. However, the therapeutic potential of FFA2 agonists for treatment of atopic dermatitis has not been investigated. We investigated the efficacy of the FFA2 agonist, 4-chloro-α-(1-methylethyl)-N-2-thiazoylylbenzeneacetanilide (4-CMTB), for treatment of atopic dermatitis induced by 2,4-dinitrochlorobenzene (DNCB). Long-term application of DNCB to the ears of mice resulted in significantly increased IgE in the serum, and induced atopic dermatitis-like skin lesions, characterized by mast cell accumulation and skin tissue hypertrophy. Treatment with 4-CMTB (10 mg/kg, i.p.) significantly suppressed DNCB-induced changes in IgE levels, ear skin hypertrophy, and mast cell accumulation. Treatment with 4-CMTB reduced DNCB-induced increases in Th2 cytokine (IL-4 and IL-13) levels in the ears, but did not alter Th1 or Th17 cytokine (IFN-γ and IL-17) levels. Furthermore, 4-CMTB blocked DNCB-induced lymph node enlargement. In conclusion, activation of FFA2 ameliorated DNCB-induced atopic dermatitis, which suggested that FFA2 is a therapeutic target for atopic dermatitis.

• Biomolecules & Therapeutics
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• v.29 no.4
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• pp.427-433
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• 2021

Free fatty acid receptor 2 (FFA2, also known as GPR43), a G-protein-coupled receptor, has been known to recognize short-chain fatty acids and regulate inflammatory responses. FFA2 gene deficiency exacerbated disease states in several models of inflammatory conditions including asthma. However, in vivo efficacy of FFA2 agonists has not been tested in allergic asthma. Thus, we investigated effect of 4-chloro-α-(1-methylethyl)-N-2-thiazoylylbenzeneacetanilide (4-CMTB), a FFA2 agonist, on antigen-induced degranulation in RBL-2H3 cells and ovalbumin-induced allergic asthma in BALB/c mice. Treatment of 4-CMTB inhibited the antigen-induced degranulation concentration-dependently. Administration of 4-CMTB decreased the immune cell numbers in the bronchoalveolar lavage fluid and suppressed the expression of inflammatory Th2 cytokines (IL-4, IL-5, and IL-13) in the lung tissues. Histological studies revealed that 4-CMTB suppressed mucin production and inflammation in the lungs. Thus, results proved that FFA2 functions to suppress allergic asthma, suggesting 4-CMTB activation of FFA2 as a therapeutic tool for allergic asthma.

• Journal of Ginseng Research
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• v.44 no.2
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• pp.350-361
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• 2020

Background: Black ginseng (BG) is a type of Korean ginseng prepared by steaming and drying raw ginseng to improve the saponin content. This study examined the effects of BG on nonalcoholic fatty liver disease (NAFLD) in HepG2 cells and diet-induced obese mice. Methods: HepG2 cells were treated with free fatty acids to induce lipid accumulation before supplementation with BG. NAFLD-induced mice were fed different doses (0.5%, 1%, and 2%) of BG for 8 weeks. Results: BG significantly reduced lipid accumulation and expression of lipogenic genes, peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein alpha, sterol regulatory element-binding protein-1c, and fatty acid synthase in HepG2 cells, and the livers of mice fed a 45% high-fat diet with 10% fructose in the drinking water (HFHF diet). BG supplementation caused a significant reduction in levels of aspartate aminotransferase and alanine aminotransferase, while antioxidant enzymes activities were significantly increased in 45% high-fat diet with 10% fructose in the drinking water diet-fed mice. Expression of proliferator-activated receptor alpha and carnitine palmitoyltransferase I were upregulated at the transcription and translation levels in both HepG2 cells and diet-induced obese mice. Furthermore, BG-induced phosphorylation of AMP-activated protein kinase and acetyl CoA carboxylase in both models, suggesting its role in AMP-activated protein kinase activation and the acetyl CoA carboxylase signaling pathway. Conclusion: Our results indicate that BG may be a potential therapeutic agent for the prevention of NAFLD.

• Proceedings of the PSK Conference
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• 2003.04a
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• pp.198-199
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• 2003

Chronic inflammatory processes are associated with pathology of Alzheimer's disease(AD). The expression of both cyclooxygenase-2(COX-2) and phospholipase A2(PLA2) appears to be strongly activated during AD, indicating the importance of inflammatory gene pathways as a response to brain injury. Stimulation of heterotrimeric G protein-coupled receptors including muscarinic receptors activates cytosolic PLA2 and receptor-mediated activation of PLA2 generates free fatty acids (i.e., arachidonic acid). (omitted)

• Natural Product Sciences
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• v.25 no.2
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• pp.165-171
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• 2019

Although the functions of a standardized extract of Gingko biloba leaves (EGb $761^{(R)}$) has been reported with regard to neurobiological properties, no attention has been paid to the impact of EGb $761^{(R)}$ on the neuronal regulation of energy homeostasis. To evaluate the hypothesis that EGb $761^{(R)}$ affect the secretion of peptide tyrosine tyrosine (PYY) and the activation of free fatty acid receptor 4 (FFA4), which are involved in the neuronal circuitries that control energy homeostasis by inducing the transfer of information about the influx of energy to the brain, we examined whether EGb $761^{(R)}$ can stimulate PYY secretion in the enteroendocrine NCI-H716 cells and if EGb $761^{(R)}$ can activate FFA4 in FFA4-expressing cells. In NCI-H716 cells, EGb $761^{(R)}$ stimulated PYY secretion and the EGb $761^{(R)}$-induced PYY secretion was involved in the increase in intracellular $Ca^{2+}$ concentration and the activation of FFA4. Furthermore, in FFA4-expressing cells, EGb $761^{(R)}$ activated FFA4. These results suggest that EGb $761^{(R)}$ may affect the control of energy homeostasis via the regulation of PYY secretion and FFA4 activation.

• Journal of Ginseng Research
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• v.47 no.4
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• pp.572-582
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• 2023

Background: Free fatty acid-induced lipotoxicity is considered to play an important role in pancreatic β-cell dysfunction. The effect of ginsenosides on palmitic acid-induced pancreatic beta-cells cell death and failure of glucose-stimulated secretion of insulin (GSIS) was evaluated in this study. Methods: Enzyme-linked immunosorbent assay kit for a rat insulin was used to quantify glucose-stimulated insulin secretion. Protein expression was examined by western blotting analysis. Nuclear condensation was measured by staining with Hoechst 33342 stain. Apoptotic cell death was assessed by staining with Annexin V. Oil Red O staining was used to measure lipid accumulation. Results: We screened ginsenosides to prevent palmitic acid-induced cell death and impairment of GSIS in INS-1 pancreatic β-cells and identified protopanaxadiol (PPD) as a potential therapeutic agent. The protection effect of PPD was likely due to a reduction in apoptosis and lipid accumulation. PPD attenuated the palmitic acid-induced increase in the levels of B-cell lymphoma-2-associated X/B-cell lymphoma 2, poly (ADP-ribose) polymerase and cleaved caspase-3. Moreover, PPD prevented palmitic acid-induced impairment of insulin secretion, which was accompanied by an increase in the activation of phosphatidylinositol 3-kinase, peroxisome proliferator-activated receptor γ, insulin receptor substrate-2, serine-threonine kinase, and pancreatic and duodenal homeobox-1. Conclusion: Our results suggest that the protective effect of PPD on lipotoxicity and lipid accumulation induced by palmitic acid in pancreatic β-cells.

• Environmental Mutagens and Carcinogens
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• v.17 no.2
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• pp.78-91
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• 1997

Peroxisome is a single membrane-bounded organelle found in hepatic parenchymal cells and kidney tubular epithelial cells. A number of enzymes exist in peroxisome contributing to anabolic and catabolic peroxisomal functions. Extramitochontriai $\beta$-oxidation of fatty acid is a major function of peroxisome. Peroxisomes can be proliferated by many structually unrelated compounds such as hypolipidemic drugs, plasticizers, pesticides, some pharmaceutical agents and high fat diet. These chemicals, called peroxisome proliferators, act via the peroxisome proliferator activated receptor, to induce peroxisome proliferation, hepatomegaly and hepatocellular carcinoma in rodent. The clear mechanisms of peroxisome proliferator-induced hepatocarcinogenesis have been not demonstrated. Since they are not genotoxic, biochemical changes or changes in gene expressions may be involved. A free radical theory has been suggested based on the finding of oxidative damages of macromolecules by hydrogen peroxide released in the peroxisomal $\beta$-oxidation of fatty acid. Increased cell proliferation by a peroxisome proliferator has been also thought to be an important factor in the hepatocarcinogenesis as suggested in other cases of nongenotoxic carcinogenesis. The alternation of eicosanoid concentrations by peroxisome proliferators may be important in the peroxisome proliferator-induced hepatocarcinogenesis since peroxisome proliferators decrease the concentration of eicosanoids, and the peroxisome proliferator ciprofibrate-eicosanoid combination is comitogenic and costimulates some mitogenic signals in hepatocytes. All of proposed mechanisms should be considered in the peroxisome prolifrator-induced hepatocarcinogenesis.

• Journal of Life Science
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• v.21 no.7
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• pp.932-938
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• 2011

Ginsenoside Rg1 is a pharmacologically active component isolated from ginseng. The goal of this study was to clarify the beneficial effects of Rg1 on glucose and lipid metabolism in diabetic animals (db/db mice). To accomplish this, ten week old db/db mice were administered 10 mg/kg of Rg1 for 15 days. Rg1 did not influence the weight of db/db mice when compared with vehicle-treated db/db mice. The administration of Rg1 lowered fasting plasma glucose, and improved glucose tolerance. Importantly, Rg1 markedly reduced both plasma triglyceride and free fatty acids, and increased high-density lipoprotein cholesterol (HDL-C) concentrations in db/db mice. Rg1 activated promoter activity of chimeric GAL4-PPAR${\alpha}$ reporter and increased expression of peroxisome proliferator-activated receptor alpha (PPAR${\alpha}$) target genes such as carnitine palmitoyltransferase-1 (CPT-1) and acyl-CoA oxidase (ACO), which are involved in fatty acid oxidation. These findings indicated that improvement of lipid profiles by Rg1 may be associated with increased fatty acid oxidation via PPAR${\alpha}$ activation. Taken together, these results suggest that Rg1 could have beneficial effects for controlling hyperglycemia and hyperlipidemia associated with type 2 diabetes.

• Journal of Life Science
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• v.32 no.11
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• pp.855-864
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• 2022

The pharmacological efficacy of Dipterocarpus tuberculatus Roxb. has been verified in only several fields including photoaging, inflammation, hepatotoxicity, acute gastritis and osseointegration. To identify the novel functions of Dipterocarpus tuberculatus Roxb. on anti-obesity, inhibitory effect on lipid accumulation and stimulatory effect on lipolysis were investigated in MDI (3-isobutyl-1-methyl-xanthine, dexamethasone, and insulin) stimulated 3T3-L1 adipocytes treated with methanol extracts of Dipterocarpus tuberculatus Roxb. (MED). Lipogenic targets, including lipid accumulation, level of lipogenic transcription factors, and expression of lipogenic regulators, were downregulated in MDI-stimulated 3T3-L1 adipocytes treated with MED without any significant cytotoxicity. Also, MED treatment inhibited the mRNA levels of adipogenic targets including peroxisome proliferator-activated receptor (PPAR)γ and CCAAT-enhancer binding protein (C/EBP) α, as well as lipogeic targets including adipocyte fatty acid binding protein 2 (aP2) and fatty acid synthetase (FAS) in MDI-stimulated 3T3-L1 adipocytes. A similar decrease patterns were detected in Oil red O stained lipid droplets of MED treated MDI-stimulated 3T3-L1 adipocytes. Furthermore, several lipolytic targets, such as cAMP concentration, concentration of free glycerol, expression level of lipases, including ATGL, perilipin and HSL, were upregulated in MDI-stimulated 3T3-L1 adipocytes treated with MED. These results show that MED has a novel role as a lipogenesis inhibitor and lipolysis stimulator in MDI-stimulated 3T3-L1 adipocytes.

• Nutrition Research and Practice
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• v.15 no.5
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• pp.568-578
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• 2021

BACKGROUND/OBJECTIVES: Psidium guajava L. (guava) leaves have been shown to exhibit hypoglycemic and antidiabetic effects in rodents. This study investigated the effects of guava leaf extract on adipogenesis, glucose uptake, and lipolysis of adipocytes to examine whether the antidiabetic properties are mediated through direct effects on adipocytes. MATERIALS/METHODS: 3T3-L1 cells were treated with 25, 50, 100 ㎍/mL of methanol extract from guava leaf extract (GLE) or 0.1% dimethyl sulfoxide as a control. Lipid accumulation was evaluated with Oil Red O Staining and AdipoRed assay. Immunoblotting was performed to measure the expression of adipogenic transcription factors, fatty acid synthase (FAS), and AMP-activated protein kinase (AMPK). Glucose uptake under basal or insulin-stimulated condition was measured using a glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose. Lipolysis from fully differentiated adipocytes was measured by free fatty acids release into the culture medium in the presence or absence of epinephrine. RESULTS: Oil Red O staining and AdipoRed assay have shown that GLE treatment reduced lipid accumulation during adipocyte differentiation. Mitotic clonal expansion, an early essential event for adipocyte differentiation, was inhibited by GLE treatment. GLE inhibited the expression of transcription factors involved in adipocyte differentiation, such as peroxisome proliferator-activated receptor 𝛄 (PPAR𝛄), CCAAT/enhancer-binding protein α (C/EBPα), and sterol regulatory element-binding protein-1c (SREBP-1c). FAS expression was also decreased while the phosphorylation of AMPK was increased by GLE treatment. In addition, GLE increased insulin-induced glucose uptake into adipocytes. In lipid-filled mature adipocytes, GLE enhanced epinephrine-induced lipolysis but reduced basal lipolysis dose-dependently. CONCLUSIONS: The results show that GLE inhibits adipogenesis and improves adipocyte function by reducing basal lipolysis and increasing insulin-stimulated glucose uptake in adipocytes, which can be partly associated with antidiabetic effects of guava leaves.